Draft Guidance for Industry: Use of Metabolite Data in Comparative Bioavailability Studies

2004-05-28
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Notice

Release of Draft Guidance Document: Use of Metabolite Data in Comparative Bioavailability Studies

The above referenced draft guidance was released by Health Canada for consultation and is being posted on the Therapeutic Products Directorate Website¹ for information and comment.

Drugs and health products activities consultation
¹ As a PDF file format under Activities/Consultation

In November 2003, the Scientific Advisory Committee on Bioavailability & Bioequivalence made final recommendations concerning the use of metabolite data in comparative bioavailability studies. Please find attached the Therapeutic Products Directorate (TPD) Draft Guidance which outlines bioequivalence requirements based on those recommendations.

Your comments are requested on this draft guidance by August 13, 2004. The TPD will consider any comments received in the finalization of this guidance. Your comments or questions should be sent to:

Dr. Conrad Pereira
Senior Scientific Advisor
Therapeutic Products Directorate
Holland Cross, Tower B
1600 Scott Street, (Rm. 2108)
Ottawa, Ont. K1A 1B6
AL# 3102C3

Tel: 613-957-6445
Fax: 613-941-5035
Email: Conrad_Pereira@HC-SC.GC.CA

Foreword

Guidance documents are meant to provide assistance to industry and health care professionals on how to comply with the policies and governing statutes and regulations. They also serve to provide review and compliance guidance to staff, thereby ensuring that mandates are implemented in a fair, consistent and effective manner.

Guidance documents are administrative instruments not having force of law and, as such, allow for flexibility in approach. Alternate approaches to the principles and practices described in this document may be acceptable provided they are supported by adequate scientific justification. Alternate approaches should be discussed in advance with the relevant program area to avoid the possible finding that applicable statutory or regulatory requirements have not been met.

As a corollary to the above, it is equally important to note that Health Canada reserves the right to request information or material, or define conditions not specifically described in this guidance, in order to allow the Department to adequately assess the safety, efficacy or quality of a therapeutic product. Health Canada is committed to ensuring that such requests are justifiable and that decisions are clearly documented.

This document should be read in conjunction with the accompanying notice and the relevant sections of other applicable guidances.

Table of Contents

1. Purpose
2. Background
3. Scope
4. Guidance

1. Purpose

To define when the use of metabolite data rather than data on the parent drug is acceptable for comparative bioavailability studies.

2. Background

The TPD guideline Conduct and Analysis of Bioavailability and Bioequivalence Studies Part A: Oral Dosage formulations used for Systemic Effect (1992) (Guideline A) is not sufficiently clear as to when it may be acceptable to use metabolite data in comparative bioavailability studies.

For example, the guideline states:

"If the test and reference products have the same galenic form and contain the same dose of the same active ingredient(s) they are said to be bioequivalent when the profiles for the drug or metabolite(s) or both are similar. (Section 1.1, 4th paragraph)

and

Bioequivalence is usually established by measuring the drug or its metabolites or both in plasma (or blood or serum). (Section 1.1, 6th paragraph).

However no guidance is provided as to the conditions under which metabolite data may be used.

The guideline also states:

The determination of bioavailability is dependent upon the reliable, precise and accurate measurement of the active ingredient, or its metabolites, or both, as a function of time. Normally, measurement of the parent compound or active ingredient will be adequate; however, in certain circumstances, the measurement of metabolites could be required. When a pro-drug is administered, the active component should be measured. (Section 6.1)

Again, it is not clear under what circumstances metabolite data could be used or if these data would be required in addition to data on the parent drug. In the case of a pro-drug, it is not clear whether only the active component should be measured or both the active component and the pro-drug.

This guidance document will serve to clarify the requirements indicated in Guideline A.

3. Scope

This guidance applies to all comparative bioavailability studies. That is, it applies to all cases where bioequivalence of a test product to a reference product constitutes the primary evidence of the safety and efficacy of the test product, regardless of the submission type (e.g.~**~, ANDS, S/ANDS, NDS, S/NDS, DIN).

4. Guidance

Determination of bioequivalence should be based on data for the parent drug.

Waiver of the measurement of the parent drug will not be considered, unless concentrations of the parent drug cannot be reliably measured, e.g., if the parent drug is not detectable due to rapid biotransformation or limitations in available assay methodology. In such instances, the use of metabolite data may be acceptable. The measured metabolite should be a primary (first step) and major one, and appropriate scientific justification for a waiver of the measurement of the parent drug and the use of metabolite data should be provided. The choice of using the metabolite instead of the parent drug is to be clearly stated, a priori, in the objective of the study in the study protocol.

For the purpose of this guidance, a pro-drug is to be treated as a 'parent drug'. That is, if the substance released from the dosage form is absorbed intact and is reliably measurable in the systemic circulation, it should be used in the assessment of bioequivalence.

It is not generally considered necessary to measure both parent drug and metabolite levels for the purpose of bioequivalence assessment. However, quantitation of metabolite levels may sometimes be helpful, e.g., to explain extreme values caused by metabolic changes within a subject.

In those rare situations where use of drug concentrations in urine is justifiable for the assessment of relative bioavailability, only parent drug concentrations may be used. That is, use of metabolite concentrations in urine is not considered acceptable in the assessment of bioequivalence.